Lowering excessive serum lipid concentrations and preparations containing fluoro-pyridine derivatives

ABSTRACT

A METHOD OF LOWERING EXESSIVE LIPID AND FREE FATTY ACID CONCENTRATION IN SERUM OF ANIMALS, INCLUDING MAN, COMPRISES ADMINISTERING A COMPOSITION CONTAINING AS THE ACTIVE INGREDIENT A THERAPEUTICALLY EFFECTIVE DOSE OF AT LEAST ONE COMPOUND SELECTED FROM THE GROUP CONSISTING OF PYRIDINE DERIVATIVES OF THE GENERAL FORMULA   3-R,5-F-PYRIDINE   AND THERAPEUTICALLY ACCEPTABLE SALTS THEREOF. THE ACTIVE INGREDIENTS EXHIBIT VISODILATING PROPERTIES. PHARMACEUTICAL PREPARATIONS CONTAINING THE PYRIDINE DERIVATIVES AS ACTIVE INGREDIENTS ARE ALSO DISCLOSED.

United States Patent LOWERING EXCESSIVE SERUM 'LIPID CONCEN- TRATIONS AND PREPARATIONS CONTAINING FLUORO-PYRIDINE DERIVATIVES Lars Anders Fritz Carlsson, Forfattarvagen 27, Bromma, Sweden; Ake John Erik Helgstrand, Baverstigen 32, Enliorna, Sweden; and Berndt Olof Harald Sjoberg, Kummelvagen 24; and Nils Erik Stjernstrom, Tappgatan 9, both of Sodertalje, Sweden I No Drawing. Continuation-impart of application Ser. No. 689,751, Nov. 15, 1967, now PatentNo. 3,637,714. This application Aug. 20, 1971, Ser. No. 173,678 Claims priority, applilcation Sweden, Nov. 16, 1966,

7/66 Int. Cl. A01n 9/22; A61k 15/12 US. Cl. 424-263 Claims ABSTRACT OF THE DISCLOSURE A method of lowering excessive lipid and free fatty acid concentration in serum of animals, including man, comprises administering a composition containing as the active ingredient a therapeutically eifective dose of at least one compound selected from the group consisting of pyridine derivatives of the general formula and therapeutically acceptable salts thereof. The active ingredients exhibit vasodilating properties. Pharmaceutical preparations containing the pyridine derivatives as active ingredients are also disclosed.

This application is a continuation-in-part application of our copending parent application Ser. No. 689,751, filed 'Nov. 15, 1967, now US. Pat. 3,637,714.

The present invention relates to serum lipid lowering pyridine derivatives having vasodilating properties and pharmaceutical preparations containing them. The invention also relates to a method for lowering excessive concentration of free fatty acids in serum of animals, including man.

In view of accumulating evidence indicating that excessive serum lipid concentration is correlated to basic pathogenetic mechanisms and to symptomsof several diseases such as vascular diseases, diabetes mellitus, and hyperthyroidism, lowering of serum lipid concentration is important during treatment of such diseases.

The lowering of serum lipid concentration may be obtained by inhibition of lipid mobilization, e.g. by'a de---' crease in the net release of lipids to the circulation in the form of free fatty acids, from stored triglycerides 'in adipose tissue.

It has now been found that compounds of the general formula and therapeutically acceptable salts thereof have vasodilating properties and are of particular value for lowering of excessive serum lipid and free fatty acid concentration, in which formula R is a radical selected from the group consisting of 'ice Patented June 5, 1973 -ooocn I -ooocn r,

-oniooowrmr-ooocnrm-r,

CH2OCOOH=CHCOOCH I F,

i --OHiO 00 N and i The expression therapeutically acceptable salt is reci ognized in the art to designate an acid additionusalt which is physiologically innocuouswhen administered in a dosage and at an interval (e.g. frequency of administration) that is effective for the indicated therapeutic use of the parent compound. Typical therapeutically acceptable acid addition salts include but are not limited'to the salts of mineral acids, such as ,hydrochloric, hydrobromic, phosphoric or sulphuric acid, organic acids such as acetic,

lactic, levulinic, citric, fumaric, maleic, succinic, tartaric, benzoic acid and sulphonic acids, such as methane sulphonic acid and sulphamic acid.

Suitable processes for the preparation of the above mentioned compounds are illustrated below. All the illustrated methods of preparation are known in the art. The compounds used as starting materials in the different processes may be prepared according to known methods.

The compound of the formula F coon may be prepared, for example, as described by Roe in U.S. Pat. No. 2,5l6,83 0;"by carbonation of Grignard reagents (X is halogen) F- Mg-X Col 1 or by oxidation of thecorresponding alcohol or aldahyde.

reacting a compound of the formula The compound of Formula -II may also beprepared by HzN- C O OH with sodium nitrite and fluoboric acid in an aqueous solution and heating the fluoborate salt thus formed to the formation of a compound of the formula Preferably the reaction of the aminonicotinic acid is carried out in a cooled Water solution also containing tetrahydrofuran.

diimidazoleor nate, X-being a metal carboxylategroup when Y is halo- .geny-whereafter the compound of Formula III thus ob- The compounds of the formula wherein is a member of the group consisting of (III) -on;- In

may be prepared by reacting a compound of the formula and wherein, in Formulas IV and V, B has the meaning specified above, Y is halogen or a hydroxy group and X is car- 'boxyl, a metal carboxylate group or an activated carboxyl group, in which case the compound of Formula IV is an acid-chloride, an alkylester, an acid anhydride or a mixed .anhydride with alkoxy formic acids, carboxylic acids, sulxphonicor inorganic acids or derivatives obtained by a reaction between a carboxylic acid and a carbodiimide or 'similarlyfunctioning compounds such as N,N'-carbonyl- N-ethyl-S-phenylisoxazolium-3'-sulphotained if necessary is transformed into a therapeutically .acceptable Saltby reaction with the appropriate acid.

The reaction may be performed in the presence of aqueous or anhydrous organic solvents such as chloroform, diethyl ether, tetrahydrofuran, benzene and toluene, or without solvents. Particularly when X represents a car I, boxyl group and Y is a hydroxy group there may be used an acid catalyst such as sulphuric acid, hydrogen chloride,

p-toluene sulphonic-acid, benzene sulphonic acid or salts Qwith h igh to intermediate acid strength, even including ion exchangers saturated with hydrogen ions. In this case, in order'togeta more favorable equilibrium, the Water 'formed during the reaction may be removed from the reaction mixture by azeotropic distillation or taken up by drying agents such as anhydrous cupric or manganese sulphate and molecular sieves. When the compound of Formula IV is an acid halide, the hydrogen halide liberated may be neutralized and the reaction catalyzed by a base such as pyridine and triethylamine.

Compounds-of the formula I l cur-o-d-n' I N v I (vi) wherein B' is selected from the class consisting of CH s)3, 2 2 2)G s,

and 7 may be prepared by reacting a compound of the formula F I CH2-Y with a compound of the formula I X B' (VIII) wherein X, Y and B have the meaning specified above. The reaction conditions are the same as for preparation of the nicotinic acid esters. The compounds of Formula VI thus obtained are transformed, if necessary, into a therapeutically acceptable salt by reaction with the appropriate acid. T Diestersof pyridine of the general formulas I I F I -o '-oi-B" N (ix and wherein, in Formula IX, D is selected from the group consisting of (CH (CH and -CH CH=CH-CH and B"is the radical;

or, provided D is CH B may also be and wherein, in Formula X, D" is selected fromthe class consisting of 2)2-, 2)4, 2)6-, and CH=CH, may be prepared'by reacting compounds of the formulas and F I -CH,-Y

respectively, with compounds of the formulas respectively, with compounds of the formula Y-CEQF respectively, wherein X and Y have the meaning specified previously. The reaction conditions are the same as for preparation of the nicotinic acid esters.

In the case where the compounds of Formula IX, when B" is the radical and respectively they can be prepared by reacting compounds of the formulas and respectively, with compound: of the formulas YD'Y and

respectively, wherein X and Y have the meaning specified above. The reaction conditions are the same as for preparation of the nicotinic acid esters.

To prepare the compound of the formula or a salt thereof, wherein X is a formyl, carboxy, chlorocarbonyl, alkoxycarbonyl, thiolester or a cyano group, is reduced by methods known to be applicable to the reduction of the unsubstituted analogues, for examyle, catalytical hydrogenation and reduction by means of a complex metal hydride, to the formation of a compound of the Formula XI and, where a therapeutically acceptable salt is required, reacting the compound of Formula XI with an appropriate acid.

According to a preferred embodiment, a compound of the Formula XII, wherein X is an alkoxy carbonyl group of at most carbon atoms, is reduced by means of complex metal hydrides, such as sodium or potassium'borohydride and lithium aluminum hydride. In cases when potassium or sodium borohydride is used as the reducin agent, the reaction may be performed in such solvents as methanol, ethanol, water or mixtures thereof. When lithium aluminum hydride is used as the reducing agent, the reaction is preferably performed in inert solvents such as diethyl ether and tetrahydrofuran.

The compound of Formula XI may also be prepared by treating an amine of the formula with a nitrite such as sodium nitrite in a water solution under such conditions that the intermediate diazonium compound decomposes and reacts with water to form an alcohol.

In treating animals, including man, the compounds of the invention may be administered orally or by injection in the form of pharmaceutical preparations comprising a therapeutically eifective amount of at least one of the previously disclosed pyridine derivatives as the active ingredient. The active ingredient may be present either as a free base or as a therapeutically acceptable acid addition salt, e.g. the hydrochloride, hydrosulphate, or the like, in association with a pharmaceutically acceptable carrier. The active ingredient may be a mixture of one or more fluoropyridine derivatives according to the invention or a mixture of their salts or a combination of different compounds and salts. Accordingly, terms relating to the novel compounds of this invention whether generically or specifically are intended to include both the free base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples, would beinconsistent with the broad meaning. The carrier may be a solid, semisold or liquid diluent or an ingestible capsule. Pharmaceutical preparations containing at least one of the novel compounds as the active ingredient constitute a further aspect of this invention. Usually the active substance will constitute between 0.1 and by weight of the preparation, more especially between 0.5 and 20% by Weight for preparations intendedfor injection and between 2 and 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin; cellulose derivatives, or gelatin, and a lubricant such as magnesium stearate, calcium stearate, a polyethylene glycol wax and the like, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may, for example, contain gum arabic, gelatin, talcum, titanium dioxide, or the like. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvent. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active components or different amounts of the active compound.

By using several layers of the active drug, separated by slowly dissolving coats, sustained release tablets are obtained. Another way of preparing sustained release tablets is to divide the dose of the active drug into granules with coats of different thickness and compress the granules into tablets together with the carrier substance. The active substance can also be incorporated in slowly dissolving tablets made for instance of fat and wax substances or evenly distributed in a tablet of an insoluble substance such as a physiologically inert plastic substance.

Effervescent powders are prepared by mixing the active ingredient with non-toxic carbonates or hydrogen carbonates, such ascalcium carbonate, potassium carbonate and potassium hydrogen carbonate, solid, non-toxic acids such as tartaric acid and citric acid.

For the preparation of soft gelatin capsules (pearl shaped closed capsules) consisting of gelatin and for example glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatin capsules may contain granulates of the active substance in combination with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, a starch (e.g. potato starch, corn starch or amylopectin) a cellulose derivative or gelatin.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from 0.2% to 20% by weight of the active substance, the balance being sugar and a mixture of ethanol, water, glycerol, and propylene-glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent.

Solutions for parenteral application by injection can comprise aqueous solutions of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of 0.5% to 10% by weight. These solutions may also contain stabilizing agents or buffering agents, or both and may conveniently be provided in various dosage unit ampoules.

The following examples illustrate the invention:

A mixture of S-aminonicotinic acid (108 g.) in 700 ml.

of fluoboric acid (48-50% w./w.), 530 ml. of tetrahydrofuran and 350 ml. of water was cooled in an ice-salt bath and with-stirring sodium nitrite (71 g.) in .a saturated water solution'was added at such a rate that the:temperature was lower than 3" C. 350 ml. of tetrahydrofuranwas added and the mixture stirred for one hour at C. .to C. The precipitate formed was filtered off and thoroughly washed with cold ethanol, cold ether and petroleum ether until it was nearly colorless. This fluoborate salt was transferred to a large'flask fitted with a stirrer and two reflux condensers and with about 500 ml. of dry ligroin (B.P. about 100 C.) and the flask was gently heated with an open flame at one point. An exothermic reaction started which soon spread to the whole mass of the salt. The decomposition was completed by refluxing for 30 minutes. The ligroin phase was decanted and the yellow product washed with ether. The product was dissolved in dilute aqueous sodium bicarbonate and r'eprecipitated with dilute aqueous hydrochloric acid. The precipitate was washed with water and dried to give 67 g. of weakly yellow product. This product may be purified by recrystallization, treatment with active carbon and a final sublimation to give a colorless product, M.P. 194 C. Identity was also established by IR-spectroscopy.

EXAMPLE 2 Preparation of tablets containing S-fluoronicotinic acid 100 g. of S-fiuoronicotinic acid were mixed with 50 g. of lactose and 45 g. of potato starch and moistened with a starch paste prepared from 5 g. of potato starchand distilled water, whereafter the mixture was granulated EXAMPLE 3 S-fluoronicotinic acid ethylester S-fluoronicotinic acid (43.6 g.) was refluxed for 4 hours with 550 ml. of thionyl chloride. Excess thionyl chloride was evaporated. To the acid chloride hydrochloride thus obtained 420 ml. of absolute ethanol were slowly added at room temperature. The mixture, which soon became homogenous, was refluxed for 2.5 hours. Excessethanol was evaporated and the solid residue was [treated with excess of saturated sodium hydrogen carbonatesolution to liberate the basic form of the product. 'Ihe mixture obtained was extracted three times with ether andjthe ether solution dried over sodium sulphate. Evaporation of solvent and distillation of the residue in vacuo gave 40.9 g. of nearly colorless liquid, B.P. 92-94 C. at 13 mm. Hg. nb =1.4820. Analyses-Equiv alent weight: Found 172; Calculated for C H FNO Q 169.

EXAMPLE 4 5-fluoronicotinic acid n-hexyl ester liquid, B.P. 146-147 C., n 2 =1.473.0. Analyses- Found: C, 63.98; H, 7.22; F, 8.62; N, 6.18. Calculated 01 C H FNO C,

63.98; H, 7.16; F, 8.43; N, 6.22.

EXAMPLESQH" S-fluoronicotinic acid methyl ester f 5- ilu oronicotin-icacid (6,.OO- g.) was'dissolved in a mixture of 10 ml. of concentrated sulfuric acid and 100ml.

was distilled at 13mm. Hg and gave 2.9 g. of'colorless of anhydrous methanol and the solution obtained was refluxed for 5 hours. Excess methanol was evaporated in vacuo and the residue poured on about 150 ml. of icewater. The mixture was made alkaline with solid sodium hydrogen carbonate and extracted with 4 portions of 50 ml. of ether. The ether solution was dried over anhydrous sodium sulphate, filtered and evaporated. The crystalline. colorless residue weighed 5.75 g. and melted at 49:550.5 C. Recrystallization from petroleum ether gave 4.85 g. of colorless crystals melting at 50-50.5 C. Equivalent Weight: Found 158.7; calculated for EXAMPLE 6 S-fluoronicotinic acid allylester A solution of S-fluoronicotinic acid chloride in pyridinechloroform was prepared in the following way. S-fluoronicotinic acid (33.0 g.) was refluxed with thionyl chloride (130 ml.) for 4 hours. The excess of thionyl chloride was evaporated under reduced pressure and then anhydrous chloroform (110 ml.) followed by anhydrous pyridine (45 ml.) was added. The mixture was heated at C. for a few minutes and then cooled in an ice-bath. To this solution (42 ml. out of a total volume of 184 ml.) a solution of freshly distilled allyl alcohol (2.9 g.) in anhydrous chloroform (20 ml.) was added with stirring during 15 minutes. The reaction mixture was allowed to stand 20 hoursat room temperature and was then added to a small-amount of water. The chloroform layer was separated, washed twice with a saturated sodium bicarbonate solution and once with water, and then dried over anhydrous sodium sulfate. Evaporation of the chloroform gave 7.5 g. yellow oil, which was purified by distillation in vacuo to give 5.6 g. colorless liquid. B.P. 99-l01 C./ 12 mm., n ==1.4953. AnalysesFound: C, 59.47; H, 4.52; F, 10.71; N, 7.92%. Calculated for C H FNO C, 59.67; H, 4.45; F, 10.49; N, 7.73%.

By the same procedure and using the same solution of S-fluoronicotinic acid chloride, the following esters were prepared:

S-fluoronicotinic acid butylester, yield 60%, B.P. 113- 114 C./12 mm., n =1.4764; Equivalent weight: Found: 200; calculated: 197.

5 fluoronicotinic acid iso-propylester, yield 60%, B.P. 9091 C./'12 mm., n =1.4734. Analyses-Found: C, 58.78; H, 5.33; F, 10.25; N, 7.81%. Calculated for C H FNO C, 59.01; H, 5.50; F, 10.37; N, 7.65%.

5-fluoronicotinic acid l-undecylester, yield 60%, B.P. 153-155 C./0.1 mm. Hg, n =1.47ll. Analyses- Found: C, 69.20; H, 8.41; F, 6.30; N, 4.93%. Calculated for C H FNO C, 69.15; H, 8.87; F,'6.43; N, 4.74%.

, By'the same procedure, but using a benzene solution of -5-fluoronicotinic acid chloride, S-fiuoronicotinic acid cyclohexylester was prepared: Yield 60%, B.P. 104-106 C./ 1.0-1.3 mm., n =l.5017. AnalysesFound: C, 64.70; H, 6.47; F, 8.57; N, 6.19%. Calculated for C H FNO z C, 64.56; H, 6.32; F, 8.51; N, 6.28%.

EXAMPLE 7 S-fluoro-3-pyridinemethyl-5-fluoronicotinate -in 15 ml. of chloroform was added with stirring during 30 minutesrThereaction mixture was stirred at room temperature for 2 hours and Was'then allowed to stand overnight. The-mixture was poured out on ice-water and the chloroform phase separated and washed twice with a saturated aqueous solution of sodium hydrogen carbonate. The chloroform solution was dried over anhydrous sodium sulfate; filtered and the solvent evaporated to give 9.0 g. of nearly colorless product, M.P. 1955-1060 C. Analyses-Found C, 57.84; H, 3.35; F, 15.41; N, 11.11%. Calculated for C H F N O C, 57.60; H, 3.22; F, 15.19; N, 11.20%.

The following compound was prepared in an analogous way:

3-pyridinemethyl S-fluoroincotinate Yield 75%, M.P. 56.657.0 C. (prisms) and 62.0- 63.0 C. (needles). Analyses-Found C, 62.21; H, 4.02; F, 8.35; N, 12.03%. Calculated for C H -FN O C, 62.07; H, 3.91; F, 8.18; N, 12.07%.

EXAMPLE 8 -fluoro-3-pyridinemethyl 5-fluoronicotinate To a stirred suspension of S-fluoronicotinic acid (7.05 g.) and 5-fluoro-3-pyridinemethanol (6.35 g.) in 70 ml. of anhydrous dioxane, a solution of N,N-dicyclohexylcarbodiimide (10.3 g.) in 50 ml. of anhydrous dioxane was added during one hour with ice-cooling. The reaction mixture was stirred at room-temperature during 16 hours and was then poured on a small amount of cold ethyl acetate. The urea precipitated was filtered oil and the filtrate evaporated. The yellow semi-solid residue was dissolved in a small amount of chloroform, put on a short column of aluminum oxide and eluated with 200 ml. of chloroform. The residue after evaporation of the chloroform solution was recrystallized from petroleum ether with a little ethanol added. The product, 4.2 g., M.P. 105- 106 C., was identical with the one prepared according to Example 7.

EXAMPLE 9 5-fluoro-3-pyridinemethyl nicotinate Nicotinic acid (3.7 g.) was refluxed 1 hour with thionyl chloride (11.9 g.). Evaporation of excess thionyl chloride gave 4.95 g. of crude nicotinic acid chloride hydrochloride, which was covered with 10 ml. of anhydrous benezene. To this mixture a solution of 5-fluoro-3-pyridinemethanol in a mixture of 12 ml. of triethylamine and 40 ml. of benzene was added with stirring. The resulting mixture was refluxed for 5 hours. After cooling the triethylamine hydrochloride was filtered off and washed with benzene. The combined washings and the filtrate were evaporated in vacuo to give a semi-solid residue. The crude product was recrystallizedfrom petroleum ether to give 3.5 g. of crystals with M.P. 65-67.5 C. Repeated recrystallizatious from petroleum ether gave a completely colorless product with M.P. 68.5-69.5 C. AnalysesCalculated for C H FN O C, 62.07; H, 3.91; F, 8.18; N, 12.07; 0, 13.78%. Found: C, 62.03; H, 3.87; F, 8.05; N, 12.14%.

EXAMPLE 10 3-pyridineethyl 3-pyridineacetate A mixture of 3-pyridineacetic acid (10.4 g.) 3-pyridinemethanol (9.3 g.) and concentrated sulfuric acid (10 ml.) in 200 ml. of benzene was refluxed during 6 hours. The reaction water formed was continually taken away by azeotropic distillation. The benzene phase was decanted and the oily residue dissolved in 50 ml. of cold water and the solution made alkaline with aqueous sodium carbonate. The alkaline mixture was extracted several times with diethyl ether, the extract dried over anhydrous potassium carbonate, filtered and the solvent evaporated to give 9.1 g. product. Distillation in vacuo gives 7.3 g. product, B.P. 162l62.5 C./0.3 mm. Hg; n =1.5540; hydrochloride M.P. 126l27 C. Analyses (hydrochloride)-F0und: C, 52.8; H, 5.26; N, 8.76; O, 9.96; Cl, 22.65%. Calculated for C H N O Cl C, 53.34; H, 5.12; N, 8.89; O, 10.15; Cl, 22.49%.

In an analogous way the following compounds were prepared:

5-fluoro-3-pyridinemethyl 3-pyridinebutyrate Reflux period 70 hours with p-toluenesulfonic acid instead of sulfuric acid. Yield 60%, n =1.535. AnalysesFound: C, 65.55; H, 5.49; F, 6.80; N, 10.40%. Calculated for C H FN O C, 65.68; H, 5.51; F, 6.93; N, 10.21%.

5-fluoro-3-pyridinemethyl 3-pyridineacetate Reflux period 20 hours with p-toluenesulfonic acid instead of sulfuric acid. Yield 60%. M.P. 58.0-60.0 C. Analyses-Found: C, 63.33; H, 4.77; F, 7.55; N, 11.53%. Calculated for C H FN O C, 63.41; H, 4.50; F, 7.72; N, 11.38%.

EXAMPLE 11 Pyridine-3-methyl 5-methylpyrazole-3-carboxylate S-methylpyrazole-3-carboxylic acid (5.05 g.) and 3- pyridinemethanol (4.36 g.) was refluxed together with p-toluenesulfonic acid monohydrate (19 g.) in ml. of benzene. A water-separator was used in order to withdraw the water in the reaction mixture. After 27 hours the benzene phase of the reaction mixture was decanted and the residue treated with excess aqueous sodium bicarbonate. The aqueous mixture was extracted with the decanted benzene phase and three portions of chloroform. The combined extracts were dried over anhydrous sodium sulfate, filtered and the solvent evaporated to give 4.9 g. of a yellow oil which spontaneously crystallized upon cooling. After recrystallization from benzene the product melted at 123.5124.5 C. AnalysesFound: C, 60.5; H, 5.12; N, 19.4; 0, 14.9%. Calculated for C H N O C, 60.82; H, 5.11; N, 19.34; 0, 14.73%.

In an analogous way using toluene as solvent, the following esters were also prepared:

5 fluoropyridine 3 methyl 5 methylpyrazole 3- carboxylate,'yield 75%, M.P. 141.5143 C. Analyses- Found: C, 55.96; H, 4.36; F, 7.96; N, 17.75%. Calculated for C H FN O C, 56.17; H, 4.29; F, 8.08; N, 17.86%.

5-fluoropyridine-3-methyl pyrazole-3-carboxyl ate, yield 75%, M.P. 162 C.; equivalent weight found: 219; calculated 221.

' EXAMPLE 12 5-fluoro-3-pyridinemethyl acetate To 50 ml. of stirred acetic anhydride, 5-flu0r0-3-pyridinemethanol (10.2 g.) was added slowly at room temperature. The reaction solution was allowed to stand for 3 days and then excess acetic anhydride was driven off in vacuo. The residue was distilled in vacuo to give 9.3 g. of colorless product, B.P. 102105 C./ 10 mm., Hg, n =1.4850. AnalysesFound: C, 57.02; H, 4.87; F, 11.07; N, 8.45%. Calculated for C' H FNO C, 56.80; H, 4.76; F, 11.23; N, 8.28%.

EXAMPLE 13 I 5-fluoro-3-pyridinemethyl caprylate To a stirred solution of 5-fluoro-3-pyridinemethanol (3.8 g.) and 13 ml. of triethylamine in 100 ml. of anhydrous benzene, a solution of caprylic acid chloride (4.9 g.) in 25 ml. of benzene was slowly added at room temperature. The mixture was stirred for 30 minutes at room temperature and then refluxed during 2 hours. After cooling the precipitate of amine hydrochloride was filtered off and washed with benzene. The combined washings and filtrate were evaporated in vacuo to give 8.3 g. of liquid residue. This was distilled in vacuo to give 5.1 g. of nearly colorless liquid, B.P. 145150 C./0.05 mm. Hg; n =l.4730. Analyses-Found: C, 66.25; H, 7.86; F, 7.33; N, 5.60%. Calculated for C H FNO C 66.38; H, 7.96; F, 7.50; N, 5.53%.

13 EXAMPLE 14 -fluoro-3-pyridinemethyl pivalate To a well stirred and ice-cooled solution of 5-fluoro-3- pyridinemethanol (6.35 g.) and 15 ml. of triethylarnine in 100 ml. of dry benzene, a solution of pivaloyl chloride (6.0 g.) in ml. of dry benzene was added during one hour. The reaction mixture was stirred 4.5 hours at room temperature and then filtered. The filtrate was washed twice with 50 ml. of a saturated aqueous solution of sodium hydrogen carbonate and then dried over anhydrous sodium sulfate. Filtering and evaporation of the solvent gave 8.7 g. of yellow-red oil, which was distilled in vacuoto give 5.45 of colorless product, B.P. 119'-121.5 C./ 13 mm. Hg; n =1.470. Analyses-Found: C, 62.50; H, 6.53; F, 8.91; N, 6.80%. Calculated for C H FNO C, 62.54; H, 6.68; F, 8.99; N, 6.63%.

5-fluoro-3-pyridinernethyl vinylacetate was prepared in an analogous way. Yield 55%; RP. 89'91 C./0.8 mm. Hg; n =1.497. AnalysesFound: C, 61.05; H, 5.55; F, 9.63; N, 7.15% Calculated for C H FNO C, 61.53; H, 5.16; F, 9.73; N, 7.18%.

EXAMPLE 1s COOCHZ F HaC \N/ \N/ 5-fluoro3-pyridinemethyl 3-methyl-5-isoxazolecarboxy-late 3-methyl-5-isoxazolecarboxylic acid (6.35 g.), S-fluoro- 3-pyridinemethanol (6.35 g.) and p-toluenesulfonic acid monohydrate (14.3 g.) was refluxed 47 hours in 100 ml. of toluene. The water in the reaction mixture was continuously removed by azeotropic distillation. The residue after evaporation of the solvent was treated with an excess of saturated aqueous solution of sodium hydrogen carbonate. The precipitate was filtered off and recrystallized from diisopropyl ether to give 4.75 g. weakly yellow product, M.P. 7981 C., which could be raised to 80.0-

8l.5 C. by repeated recrystallizations from diisopropylether. AnalysesFound: C, 54.35; H, 3.80; F, 8.31; N, 11.90%. Calculated for C H FN O C, 55.93; H, 3.84; F, 8.04; N, 11.86%.

In the same way 5-fluoro-3-pyridinemethlyl S-methyl- 3-isoxazolecarboxylic acid was prepared; M.P. 69.0- 71.5 C. AnalysesFound: C, 56.03; H, 3.97; F, 7.79; N, 11.54%. Calculated for C H FN O C, 55.93; H, 3.84; F, 8.04; N, 11.86%.

EXAMPLE 16 Diester of S-fluoronicotinic acid and ethylene glycol portions of diethyl ether. The extract was dried over an hydrous sodium sulphate, filtered and the solvent evaporated to give a crystalline residue, which was triturated with a little cold petroleum ether. Yield 6.21 g., M.P. 84-90" C. Recrystallization from diisopropyl ether gave 5.35 g. of colorless product with M.P. 91.0-91.5" C. Analyses-Found: C, 54.88; H, 33.39; F, 12.53; N, 9.05%. Calculated for C I-I F N O C, 54.55; H, 3.27; F, 12.33; N, 9.09%.

In an analogous way the following compounds were prepared:

Diester of 5-fluoronicotinic acid and hexane-1,2-diol Yield M.P. 56.056.5 C. Analyses-Found: C, 59.75; H, 5.16; F, 11.07; N, 8.17%. Calculated for c13H1 F2N204: C, H, F, N, 769%.

Diester of S-fiuoronicotinic acid and propane-1,2-diol Yield 50%; M.P. 192-194 C./0.3 mm. Hg; n =1.5200. AnalysesFound: C, 55.66; H, 4.17; F, 11.90; N, 8.54%. Oalbulatedfor C H FqN O C, 55.91; H, 3.75; F, 11.79; N, 8.69%.

Diester of S-fluoronicotinic acid and trans-2- butene-1,4-diol Yield 75%; M.P. 115.5 116.0 C. Analyses-Found: C, 57.67; H, 3.70; F, 11.24; N, 8.24%. Calculated for C15'H12F2N204: CY,

EXAMPLE 17 Diester of succinic acid and 5-fluoro-3- pyridine methanol Succinic acid (2.36 g.), 5-fluoro-3-pyridine methanol (5.1 g.) and p-toluene sulfonic acid monohydrate (10.0 g.) were refluxed 23 hours in 50 ml. of benzene. The water in the reaction mixture. was continuously removed by azeotropic distillation. The mixture was poured out on ice-water and made alkaline with sodium hydrogen carbonate. The precipitate formed was filtered off, washed with water and dried. It weighed 2.9 g., M.P. 80.0-81.0 C., after recrystallization from ether-ethanol, M.P. 80.0-81.5 C. AnalysesFound: C, 57.30; H, 4.22; F, 11.33; N, Calculated for C15H14F3N2O4I C, 57.14; H, 4.20; F, 11.30; N, 8.33%.

In an analogous way the following compounds were also prepared:

Diester of adipic acid and 5-fluoro-3-pyridine methanol Yield 65%; M.P. '57.0-57.5 C. AnalysesFound: C, 59.59; H, 4.96; F, 10.59; N, 7.70%. Calculated for C18H18F2N2O4: C, H, F, N, 7.69%.

Diester of suberic acid and S-fluQro-B-pyridine methanol Yield 45%; M.P. 63.064.0 C. AnalysesFound: C, 61.40; H, 5.60; F, 9.53; N, 7.09%. Calculated for C 'H F N O C, 61.22; H, 5.65; F, 9.68; N, 7.14%.

Diester of fumaric acid and S-fluoro- 3-pyridine methanol Yield 30%; M.P. 120.5422 C. Equivalent Weight (titration as base) Found: 167. Calculated for C H F N O 167.2. The identity and purity of the product was also established NMR spectroscopy.

EXAMPLE 18 5-fluoro-3-pyridine methanol To a stirred solution of ethyl 5-fluoronicotinate (54.1 g.) in 270 ml. of methanol, potassium borohydride (53.9 g.) was added with cooling over a period of one hour. The mixture was stirred 30 minutes at room temperature and then refluxed for 6 hours. The solution was stirred overnight at room temperature and then most of the solvent was evaporated. The residue was dissolved in 300 ml. of water and after one hour extracted with five ml. portions of ether. The ether solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to give 38 g. of a yellow oil. The oil was distilled in vacuo to give 29.6 g. colorless product, B.P. 83-85 C./0.0 50.01 mm. Hg. The hydrochloride meltsfafter repeated recrystallizations from ethanol) at 126 C. Analyses-Found: C, 44.19; H, 4.59; N, 8.70; F, 11.42; Cl, 21.52%. Calculated for C H NOFC1: C, 44.05; H, 4.32; N, 8.56; F, 11.61; Cl, 21.68%.

To a stirred ice-cooled solution of lithium aluminum hydride (14.4 g.) in 530 ml. of anhydrous ether a precooled'solution of ethyl S-fiuoronicotinate (64.3 g.) in 370 ml. of anhydrous ether was added during 1.5 hours at a reaction temperature not exceeding 6 C. The miX- ture was stirred with cooling for 30 minutes and then 72 ml. of a sodium sulfate solution in water ml./g.) was slowly added with stirring and cooling. The mixture was filtered and the solid material washed with ether, The combined ether solutions were dried, filtered and the solvent evaporated to give 36.6 g. red oil. This was converted to the hydrochloride, which after repeated recrystallizations from ethanol melts at 162 C. The product was shown to be identical with the one prepared according to Example 18.

EXAMPLE 20 S-fluoro-3-pyridinemethanol The starting material 5-fluoro-3-cyanopyridine, M.P. 53-54.5 C., was prepared by dehydration of the known S-fluoronicotinamide with phosphorus pentaoxide.

5-fluoro-3-cyanopyridine (1.50 g.) was dissolved in a mixture of 2.5 ml. of concentrated hydrochloric acid and 25 ml. of water and hydrogenated at atmospheric pressure and room temperature over Pd/C (0.40 g.). After 8 hours 535 ml. of hydrogen had been consumed. The hydrogenation was interrupted for 3 days and then further hydrogenated during one hour over an additional amount of 10% Pd/C (0.30 g.). A total amount of 600 ml. of hydrogen was consumed. The catalyst was filtered oif and washed with water. The combined filtrate and washings were concentrated to a volume of 25 ml. made alkaline by addition of solid sodium hydrogen carbonate and extracted five times with 40 ml. of butyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to give an oily residue, which was transformed to a hydrochloride salt. This prcduct, which was colorless, weighed 1.42 g. and had an IR spectrum which was identical with the one obtained from the product according to Example 18.

EXAMPLE 2i S-fluoro-3-pyridinemethan0l S-fluoronicotinic acid (3.00 g.) was refluxed 4 hours with 30 ml. of thionyl chloride and the excess of thionyl chloride evaporated in vacuo. The S-fluoronicotinc acid chloride thus obtained was dissolved in 30 ml. of diglyme and treated while stirring with sodium borohydride (2.40 g.), first minutes at 35 C. and then 30 minutes at 80 C. The mixture was poured out on ice and carefully S-fluoro-3-pyridinemethan0l The starting material S-benzyl 5-fluoro3-pyridine'carbothioate M.P. 4244 C., was prepared by the reaction of S-fluoronicotinoyl chloride with benzylmercaptan.

S-benzyl S-fluoro-3-pyridinecarbothioate 11.00 g.) was stirred 3 hours at room temperature with freshly prepared Raney nickel (W4, 10 g.) in 70 ml. of ethanol. The metal was filtered off and thoroughly washed with ethanol.

. 5-fiu0ronicotinic acid allyl ester -16 To the combined filtrate and washings were added a small excess of hydrogen chloride in ether. Evaporation of the solvent in vacuo gave the hydrochloride salt, which was washed with ether and air-dried. The colorless product weighed 0.43 g. and had an IR spectrum which was identical with the one obtained from the product according to Example 18.

EXAMPLE 23 PHARMACOLOGICAL TESTS Compounds according to the invention were tested: with regard to lowering the concentration of free fatty acids in the serum of dogs according to the method described in Carlsson, L. A. and Lil-jedahl, S. 0., Lipid metabolism and trauma. 11. Studies on the effect of 'nicotinic acid on norepinephrine induced fatty liver. Acta Med. Scand. 173 (1963), 787-791, and Bergstrorn, S., Carlsson, L. A. and 0m, L. Effect of prostaglandins on catecholarnine induced changes in the free fatty acids of plasma and'in blood pressure in the dog. Prostaglandin and related factors 22, Acta PhysioL'Scand. 60 (1964) 170-180. According to this method, the compound is tested on a model for the stress situation in which noradrenaline stimulated lipid mobilization is known to occur.

Anaesthetized dogs were given continuous intravenous infusions of noradrenaline at a constant rate (0.5 ,ug./kg. bodyweight per minute). The test substance was injected intravenously 60 min. after the start of infusion. The arterial level of free fatty acids as a function of time was followed. Nicotinic acid was used as reference. The qualitative effect is given in Table I.

The qualitative effect was judged from the total depression of free fatty acid serum concentration and the duration of the depression. The effect of each compound was judged from the relative depression a, as calculated in percent of the total rise in free fatty acid serum concentration induced by the noradrenaline infusion, and from the total duration, b (minutes) of morev than a 50% depression of free fatty acid serum concentration. The test results at a dosage level of 25 mg./kg.- are classified according to the following scheme:

a, b, percent minutes Effect 80 100 20-79 100 20-79 10 Y t m TABLE .I

' Qu'alitative Compound effect Nicotinic acid (reference) fi-fluoronicotinic acid fi-fluoronicotinic acid methyl est fi-fluoronicotim'c acid ethyl ester. Eefluoronicotinic acid n-butyl ester 5-finoronicotinic acid n-hexyl esterfi-fiuoronicotinic acid n-undecyl ester 5-fluoronicotinic acid i-propyl ester;

6-fluorom'cotinic acid cyelohexyl ester TABLE I-Continued Qualitative Compound effect I R (3]ii--O(i'---R F GEL F (CH3)3C F Hz=CH-CH3 F CHr-O-(i-O CH R JR'-O J R N N RI Ra Ra (C :)u- CH=CH-(trans.)

F CHzOH S-fluoronicotinic acid has a low toxicity. The toxicity of -fluoronicotinic acid upon i.p. administration in mice given as the LD -value was found to be 2.0 g./ kg. bodyweight. The corresponding toxicity of nicotinic acid was found to be 0.5 g./kg. bodyweight.

The resorption of S-fluoronicotinic acid in serum of dogs was studied. 200 mg. of the test compound were orally administered to the dog in the form of a tablet also containing 200 mg. of physiologically inert material. The amount of the test compound in the blood serum was analyzed at different times according to Hughes, D. E. and Williamson, D. H., Biochem. J. 55 (1953), 851. A comparison with nicotinic acid was made in each case. The maximum resorption and the duration (given as the time after administration when the serum concentration had decreased to 25% of the maximum concentration) is given in Table H.

The resorption of pyridine methanols in serum of dogs Was also studied. -200 mg. of the substance to be tested was orally administered to the dog in the form of a tablet or a capsule. The amount of the test compound was analyzed as the corresponding nicotinic acid derivative (the metabolism to these acids is very rapid) at different times according to Hughes, D. E. and Williamson, D. H., Biochem. J. 55 (1953), 851. A comparison with the unsubstituted analogue was made. The maximum resorption and the duration (given as the time after administration when the serum concentration had decreased to 25 of the maximum concentration) of the compound of Formula XIII, wherein R has specified significance is given in Table HI.

R (DH-20H N (XHI) TABLE III Admin- Maximum istered Way of resorption, Duration, R amount, g. administration -y/m1. serum hours 0.2 Tablet 47.6 3.5 0 2 32. 2 1. 7 32.2 1.7

The compound 5-fluoro 3-pyridinemethanol has a low toxicity as may be seen from Table IV below, wherein the toxicity in mice upon intraperitoneal administration of a compound of the Formula XIII is given.

TABLE IV R F Toxicity (i.p.) LD g./kg. mice 2 The compound 5-fluoro-3-pyridinemethanol was also tested with respect to its vasodilating properties. Changes in the peripheral blood flow of one hind leg of cat was recorded as follows:

The blood of the femoral artery was bypassed in a loop of polyethylene tubing inserted into the artery. The blood flow through the loop was adjusted by a digital pump. Just distal of the pump arterial pressure was measured. The pressure recorded is then dependent on the pump flow and the resistance distally of the pump. If the flow is kept constant the pressure changes will thus reflect changes in the peripheral resistance.

Intraarterial injections of S-fluoro-3-pyridinemethanol (0.1% solution in isotonic sodium chloride solution, 1 mg. substance/min.) gave 23% decrease in the vascular resistance.

EXAMPLE 24 Preparation of soft gelatin capsules containing S-fluoronicotinic acid ethylester 500 g. of S-fiuoronicotinic acid ethylester were mixed with 500 g. of corn oil whereafter the mixture was filled in soft gelatin capsules, each capsule containing 100 mg. of mixture (i.e. 50 mg. of active substance).

EXAMPLE 25 Preparation of soft gelatin capsules containing S-fluoronicotinic acid methylester 500 g. of S-fiuoronicotinic acid methylester were mixed with 750 g. of peanut oil whereafter the mixture was filled in soft gelatin capsules, each capsule containing mg. of mixture (i.e. 50 mg. of active substance).

EXAMPLE 26 Preparation of tablets containing S-fiuoronicotinic acid ethylester 50 kg. of S-fluoronicotinic acid ethylester were mixed with 20 kg. of silicon dioxide of the trademark Aerosil,

19 whereafter 45 kg. of potato starch and 50 kg. of lactose were mixed in and the mixture moistened with a starch paste prepared from kg. of potato starch and distilled water, whereafter the mixture was granulated through a sieve. The granulate was dried and sieved whereafter 2 kg. of magnesium stearate were mixed in. Finally the mixture was pressed into tablets, each weighing 172 mg.

EXAMPLE 27 Preparation of an emulsion containing S-fiuoronicotinic acid ethylester 100 g. of S-fluoronicotinic acid ethylester were dissolved in 2500 g. of peaunt oil. From the solution thus obtained, 90 g. of gum arabic, aroma and color (q.s.) and 2500 g. of water an emulsion was prepared.

EXAMPLE 28 Preparation of a syrup containing S-fiuoronicotinic acid isopropylester 100 g. of S-fluoronicotinic acid allylester were dissolved in 300 g. of 95% ethanol where 300 g. of glycerol, aroma and color (q.s.) and water 1.000 ml. Were mixed in. A syrup was thus obtained.

EXAMPLE 29 Preparation of a solution containing S-fluoronicotinic acid ethylester 100 g. of S-fluoronicotinic acid ethylether were dissolved in 2.000 g. of polyoxyethylene sorbitan monooleate, whereafter aroma and color (q.s.) and water to 5.000 ml. were mixed in. A clear drop solution was thus obtained.

EXAMPLE 30 Preparation of a syrup containing vitamins and S-fluoronicotinic acid The syrup was prepared from the following ingre- Aroma, color (q.s.). Water to 100 ml.

Vitamin A was dissolved in the polyoxyethylene sorbitan monooleate while heating to about 60 C., whereafter 20 ml. of water was mixed in. The caffeine was dissolved in ml. of water, while heating to about 90 C. The remaining ingredients were mixed in about 60 ml. of water, whereafter the vitamin A and caffeine solutions were added while stirring. The pH was adjusted to 4.5- 5.5 by addition of sodium hydroxide solution and the syrup made up to 100 ml. with water. The whole procedure was carried out in nitrogen atmosphere. A normal dose is contained in ml. of the syrup.

EXAMPLE 3 1 Preparation of a drop solution containing S-fluoronicotinic acid 100 g. of S-fluoronicotinic acid were mixed with 300 g. of ethanol, whereafter 300 g. of glycerol, water to 1.000 ml. aroma and color (q.s.) and 0.1 N sodium hydroxide solution (to pH 4.5-5.5) were added while stirring. A drop solution was thus obtained.

20 EXAMPLE 32 Preparation of a sustained release tablet containing S-fluoronicotinic acid 200 g. of 5-fluoronicotinic acid were melted together with 50 g. of stearic acid and 50 g. of carnauba wax. The mixture thus obtained was cooled and ground to a particle size of at most 1 mm. (diameter). The mass thus obtained was mixed with 5 g. of magnesium stearate and pressed into tablets each weighing 305 mg. Each tablet thus contains 200 mg. of active substance.

Thus, novel fluoro-pyridine derivatives and pharmaceutical preparations containing them are now provided which have valuable vasodilating properties and which are effec tive in lowering excessive lipid and free fatty acid concentration in serum.

While the foregoing specification is an accurate and complete disclosure, it is not intended to limit the scope of the invention as defined by the following claims.

We claim:

1. A method of lowering excessive serum lipid concentration which comprises administering to animals, including man, a therapeutically effective dose containing at least one compound selected from the group consisting of fluoro-pyridine derivatives having the formula F1 R N/ and therapeutically acceptable salts thereof, wherein R is COOH, CH OH, COOCH COOC H COOC H COOC H COOC H COOCH(CH COOCH CH=CH CHI-CH3 CHg-CHg CH OCOCH CH OCOC(CH CH OCOCH CH=CH or CH OCO(CH CH 2. The method of claim 1 wherein the compound is 5- fiuoronocotoinic acid or a therapeutically acceptable salt thereof.

3. The method of claim 1 wherein the compound is 5- fiuoro-3-pyridine methanol or a therapeutically acceptable salt thereof.

4. A method of lowering the concentration of free fatty acids in serum which comprises administering to animals, including man, a therapeutically efiective dose containing at least one compound selected from the group consisting of fluoro-pyridine derivatives having the formula 5. The method of claim 4 wherein the compound is 5- fiuoronicotinic acid or a therapeutically acceptable salt thereof.

C O O-CH 6. The method of claim 4 wherein the compound is 5- one compound selected from the group of fiuoro-pyridine fluoro-3-pyridine methanol 01' a therapeutically acceptable derivatives having the formula salt thereof.

7. A method of lowering excessive serum lipid concentration which comprises administering to animals, includ- 5 ing man, a therapeutically effective dose of at least one compound selected from the group of fiuoro-pyridine derivatives having the formula F l R and therapeutically acceptable salts thereof, wherein R is F- l R 1 \N COO--CH I and therapeutically acceptable salts thereof, wherein R is \N -o0o-oH,-

L l --COO-CH F, N l

-ooo-c11 F,

J COOCH2CH2OCO F,- N

-COOCH2CHzOCO F,

L l -ooo om)iooo F, N Ll -000 on ooo- F (m -ooo:iH-cm-oc0 F,

H9 l N -COOCH-CH 000 F l 2- -CO0CH2CH=CH-CHzOCO-- F, CH:

C 2 rl 40 -oooomomoco -COOCH2CH2000 L I -CH:OCOCH2CH2COOCH F, \N l -CH2OCOCH2CH2COOCH F,

i -CHzOCO(CH2)4COOCH F, N

N -onzooo om)icooorrr- F,

L\ CHzOCO(CH2)-OOOCHz- F,

-CH2OCO(CH2)r-COOCH I F, N

LN) -CH2O o o 011:0110 OOCHg-Q j,

-CHzOCOCH=CHC O OCHr- CH2OGO 8. A method of lowering the concentration of free fatty A mefhod of lowering $eI'uI11 1iPid f acids in serum which comprises administering to animals, tration which comprises admmlsterlng to animals, includincluding man, a therapeutically effective dose of at least ing man, a therapeutically eflective dose containing at 23 least one compound selected from the group consisting of fluoro-pyridine derivatives having the formula 10. A method for lowering the concentration of free fatty acids in serum which comprises administering to animals, including man, a therapeutically effective dose containing at least one compound selected from the group consisting of fluoro-pyridine derivatives having the formula and therapeutically acceptable salts thereof, wherein R is CH3 l t 11. A pharmaceutical preparation for lowering excessive serum lipid concentration which comprises a therapeutically effective lipid lowering amount of at least one compound of the formula or therapeutically acceptable salts thereof, wherein R is COOH, CH OH, COOCH COOC H COOC H COOC H COOC z3, COOCH(CH COOCH -CH=CH COO-CH CH OCOCH CH OCOC(CH CH OCOCH CH=CH or CH OCO(CH CH in association with a pharmaceutically acceptable carrier.

12. The pharmaceutical preparation of claim 11 wherein the compound is S-fluoronicotinic acid or a therapeutically acceptable salt thereof.

13. The pharmaceutical preparation of claim 11 wherein the compound is v5-fluoro-3-pyridine methanol or a therapeutically acceptable salt thereof.

24 14. A pharmaceutical preparation for lowering excessive serum lipid concentration which comprises a therapeutically eifective lipid lowering amount of at least one compound of the formula or therapeutically acceptable salts thereof, wherein R is -o0o o11)0oo- -oooon-oH2-ooo Ha I --COOCHaCH=CH-CHa-OCO I F,

-oooonlornoool,-

N --CHzOCOCHzCH2000CHr-(]-F,

--CH2OCO(CH2)4COOCH2- N -OHzOCO(OH2)a-COOCH I F,

--CHzO C OCH=CHCO OGHz-L in association with a pharmaceutically acceptable carrier. 15. A pharmaceutical preparation for lowering excessive serum lipid concentration which comprises a thera- 26 peutically effective lipid lowering amount of at least one and compound of the formula in association with a pharmaceutically acceptable carrier.

or therapeutically acceptable salts thereof, wherein R is References Cited n 10 UNITED STATES PATENTS N I 3,557,131 1/1971 Yoshimura 260-2955 H CH8 ALBERT T. MEYERS, Primary Examiner n N 15 A. P. FAGELSON, Assistant Examiner US. 01. X.R.

H 260294.8 R, 295.5 R, 297 R; 424-266 (L -CHa 22 g UNITED STATES PATENT OFFICE CERTIFICATE OF. CORRECTION Patent No. 3,737,542 Dated June 5, 1973 hventofls) Lars Anders Fritz Carlsson et a1.

It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected as shown below:

Col. 5 line 8, "(CH2)5CO3" should be (CH2)6CH3 C01. 5, lines 10-14,-" I 1.1

N N N i Col. 20, c1. 2, line 2, "fluoronocotoinic" should be fluoronicoti'nic Col. 21, c1. 7, formula 3 from bottom, "-CH OCO(CH -COOCH should be -CH OC0(CH -COOCH C01. 24, cl. 14, last formula,

v N. N

should be I Signed and sealed this 26th day of February 1971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. C. MARSHALL DANN M Attesting Officer Commissioner of Patents 

